Charles, Oscar James;
(2023)
Modelling the genomic structure, and antiviral susceptibility of Human Cytomegalovirus.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Human Cytomegalovirus (HCMV) is found ubiquitously in humans worldwide, and once acquired, the infection persists within the host throughout their life. Although Immunocompetent people rarely are affected by HCMV infections, their related diseases pose a major health problem worldwide for those with compromised or suppressed immune systems such as transplant recipients. Additionally, congenital transmission of HCMV is the most common infectious cause of birth defects globally and is associated with a substantial economic burden. This thesis explores the application of statistical modelling and genomics to unpick three key areas of interest in HCMV research. First, a comparative genomics analysis of global HCMV strains was undertaken to delineate the molecular population structure of this highly variable virus. By including in-house sequenced viruses of African origin and by developing a statistical framework to deconvolute highly variable regions of the genome, novel and important insights into the co-evolution of HCMV with its host were uncovered. Second, a rich database relating mutations to drug sensitivity was curated for all the antiviral treated herpesviruses. This structured information along with the development of a mutation annotation pipeline, allowed the further development of statistical models that predict the phenotype of a virus from its sequence. The predictive power of these models was validated for HSV1 by using external unseen mutation data provided in collaboration with the UK Health Security Agency. Finally, a nonlinear mixed effects model, expanded to account for Ganciclovir pharmacokinetics and pharmacodynamics, was developed by making use of rich temporal HCMV viral load data. This model allowed the estimation of the impact of immune-clearance versus antiviral inhibition in controlling HCMV lytic replication in already established infections post-haematopoietic stem cell transplant.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Modelling the genomic structure, and antiviral susceptibility of Human Cytomegalovirus |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10169477 |
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